Factor IXa inhibitors

Factor VIII process, 12 143 Factor IX, 4 86-87 Factor IXa, 4 86-87, 89 Factor IXa inhibitors, 4 103 Factor IX concentrates, properties of, 72 152t... 

Nishida H, Saiton F, Hirabayashi T, Chackalamtmnil S, Chan T-Y AU, Chellian M, Clasby MC, Dwayer MP, Greenlee WJ, Xia Y(2010) Morpholinone compounds as factor IXA inhibitors. Patent W02010065717 (Al), 10 June 2010... 

Chan, M.Y. et al. A randomized, repeat-dose, pharmacodynamic and safety study of an antidote-controlled factor IXa inhibitor. Journal of Thrombosis and Haemostasis 6,789-796,2008. 

Four naturally occurring thrombin inhibitors exist in normal plasma. The most important is antithrombin III (often called simply antithrombin), which contributes approximately 75% of the antithrombin activity. Antithrombin III can also inhibit the activities of factors IXa, Xa, XIa, Xlla, and Vila complexed with tissue factor. a2-Macroglobulin contributes most of the remainder of the antithrombin activity, with heparin cofactor II and aj-antitrypsin acting as minor inhibitors under physiologic conditions. 

Antithrombin, already mentioned in the context of heparin, is the most abundantly occurring natural inhibitor of coagulation. It is a single-chain 432 amino acid glycoprotein displaying four oligosaccharide side chains and an approximate molecular mass of 58 kDa. It is present in plasma at concentrations of 150 pig ml 1 and is a potent inhibitor of thrombin (factor Ha), as well as of factors IXa and Xa. It inhibits thrombin by binding directly to it in a 1 1 stoichiometric complex. 

Antithrombin. A serine protease inhibitor (serpin) that degrades the serine proteases of thrombin, factors IXa, Xa, XIa and Xlla. It is constantly active, but its adhesion to these factors is increased by the presence of heparin sulphate (a glycosaminoglycan) or the administration of heparins (different heparinoids increase affinity to factor Xa, thrombin, or both). Deficiency of antithrombin (inborn or acquired, e.g. in proteinuria) leads to thrombophilia. 

Proteinase inactivation occurs by a stoichiometric reaction between proteinase and inhibitor that results in the formation of a covalent ester bond between the reactive site residue of the inhibitor (Arg in antithrombin) and the active site residue (Ser in the proteinase). The proteinases thrombin, factor Xa, factor IXa, and, less effectively, factor Vila and factor XIa are all inactivated by antithrombin (Figure 36-16). Other SERPINS can inactivate procoagulant proteinases, heparin cofactor II can inactivate thrombin, and O I-proteinase inhibitor can inactivate factor Xa. An altered a i -proteinase inhibitor (a i -proteinase inhibitor... 

Likewise, benzo[6]thiophenes have also been the subject of several biologically oriented studies. The structurally rather simple sulfonamide 100 was identified as a carbonic anhydrase inhibitor <05BMCL4872>, whereas methanesulfonate salts of the guanidine derivatives lOI displayed cardioprotective activity <05BMCL2998>. A series of 5-amidinobenzo[6]thiophene derivatives have been identified as dual inhibitors of factors IXa and Xa <05BMCL29>. The... 

Antithrombin III (AT-III), a single-chain glycoprotein of 58 kDa and 480 amino acids, is synthesized in the liver. It is a serine protease inhibitor, and acts as the most important inhibitor in the coagulation cascade to avoid blood clot formation. AT-III inhibits a wide spectram of serine proteases induding thrombin, factors IXa, Xa and XIa, kaUikrein, plasmin, urokinase, Cl-esterase, and trypsin. AT-III interacts with heparin by binding to specific sul-fated and non-sulfated monosaccharide units on heparin. The binding of AT-III to heparin enhances the inhibition of factors IXa, Xa, and thrombin. 

Dalteparin, and other low molecular weight heparins, are more selective inhibitors of factors IXa and Xa than the higher weight heparins, and have less effect on the inhibition of thrombin. This primarily results because their smaller size is not conducive to the concurrent binding of antithrombin 111 and thrombin. 

A further means of inactivating the proteases of the clotting cascade is provided by a number of protease inhibitors which are present in circulating blood. The two most important are antithrombin, which binds tightly to thrombin and can also scavenge Factors IXa, X and XI when free in solution, and a-antitrypsin, which will inactivate Factor Xg even when it is bound to a phospholipid membrane. Activated clotting intermediates may also be removed by the liver and to a lesser extent by other tissues. 

There are various inhibitors within the coagulation system that counterregulate activation of the coagulation cascade. Among them, antithrombin III (AT-III) and protein C (PC) are the most important (SI). AT-III binds in the presence of heparin the activated factors F-IXa, F-Xa, and F-IIa (thrombin). PC is activated by a complex formed between thrombin and thrombomodulin, a surface protein of endothelial cells. Once activated, PC in the presence of protein S (PS) specifically degrades activated factors F-Va and F-VIIIa. PC decreases in the course of sepsis in relation to the severity of the condition (L15). Experimental studies have... 

Heparin has been found to bind a large number of proteins (Table 3). The biological activity of heparin and related polysaccharides is usually ascribed to their interaction with heparin-binding proteins. These proteins can be classified into classes including (1) enzymes, (2) protease inhibitors, (3) lipoproteins, (4) growth factors, (5) chemokines, (6) selectins, (7) extracellular matrix proteins, (8) receptor proteins, (9) viral coat proteins, (10) nuclear proteins, and (11) other proteins (1). Many heparin-binding proteins are enzymes and enzyme inhibitors. For example, proteases in the coagulation cascade, such as factors Ha, IXa, Xa, Xlla, and Villa, are heparin-... 

Heparin binds to antithrombin (a protease inhibitor that inactivates factors Ha, IXa, Xa and XIa) and markedly accelerates its inhibitory effect on coagulation. In addition, heparin inhibits platelet function, The newer low-molecular-weight heparins augment antithrombin activity preferentially against factor Xa and do not prolong the APTT like standard (unfractionated) heparin does. 

Antithrombin III is formed in the hepatocytes as an U2-globulin. It serves as a physiological inhibitor of serin proteases in the coagulation system and thus inhibits activating factors Ila, IXa, Xa, XIa and Xna. As the name implies, AT III is most effective as an inhibitor of thrombin. Half-life is 2-3 days. 

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